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Ageing & Cell Death (Study Apoptosis (Morphology, ! Proteins (caspases…
Ageing & Cell Death
Apoptosis
- organised for of cell death
- Characterised by shrinkage of the cell body
- blebbing of cell membrane
- Chromatin condensation
- Fragmentation of the nucleus
- Cleavage of chromosomal DNA
- Division into numerous cell fragments
Discoveries concerning genetic regulation of organ development and programmed cell death:
Sydney Brenner
H. Robert Horvitz
John Sulston
14 genes are associated with the apoptosis of c.elegan ced-4
- Ced-4 can induce apoptosis.
- Ced-9 can inhibit ced-3&4 and stop apoptosis
- Ced-9 deficiency can cause excessive apoptosis and fetus dies
Apoptosis important in normal physiology and development
- Development - immune system maturation, morphogenesis, neutral development
- Adult - immune privilege, DNA damage and wound repair
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Triggers of apoptosis
Inhibitory factors
- physiological
- Pathological
Activating factors
- Physiological
- Pathological
- Glutamate
- Free radicals
- Therapeutics
Major forms of cell death
- Apoptosis - self destruction - programmed cell death
- Necrosis - killing - decay and destruction
Stages in apoptosis:
- Chromosomes condense and its cytoplasm shrinks
- Nucleus becomes fragmented
- DNA is digested at regular intervals (laddering)
- Cytoplasm becomes fragmented
- Cell extends numerous blebs
- Remnants of dead cell (apoptotic bodies) ingested by phagocytic cells
Necrosis
- Chromatin clumping
- Swollen organelles
- Flocculent mitochondria
- Disintegration
- Release of intracellular contents
Inflammation
Changes in cells during apoptosis
Morphological changes:
- Shrinkage of the cell
- Fragmentation into membrane-bound apoptotic bodies and rapid phagocytosis by neighbouring cells
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Biochemical changes:
- Translocation of proteins
- Activation of caspases
- Formation of death inducing signalling complex (DISC)
- Activation of endonuclease
Process of cell death proceeds via 2 main pathways:
- Intrinsic - mitochondria-mediated)
- Extrinsic - receptor-mediated
Event occurring during extrinsic cell death
- Apoptosis receptors in cell surface are Fas and TNF receptor R1
- Fas ligand (FasL) binds. Fas and change DD structure to link to DD of Fra associated death domains (FADD)
- DED (Death effector domain) of FADD bind to caspase-8 to form death-inducing signaling complex (DISC)
Disc activate caspase 8-10 and begin a caspase cascade reactions to active caspase 3-6 and 7
Events in intrinsic cell death
- Cellular stree activate the p53 tumour-suppressor protein
- p53 initiates the intrinsic pathway by upregulating Puma and Noxa, which in turn activate Bax and Bax1
- Bax and Bak permeablise the outer mitochondrial membrane reulting in efflux of cytochrome c
- Cytochrome c binds to the adaptor Apaf-1 to recruit the initiator procaspase 9 into a signalling complex termed the apoptosome
- Activated caspase 9 then cleaves and activates the effector caspases 3,6,7 to trigger apoptosis
- Mitochondrial protein Smac/DIABLO augments apoptosis by bind inhibitor or apoptosis proteins (IAP) and reversing their grip on several caspases1
Major proteins that control apoptosis
Oncogene - BCL2 family - contain at least one Bcl-2 homology domains
Intracellular signalling peptides and proteins - Caspases - cysteine-dependent aspartate-specific proteases
Study Apoptosis
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! Proteins (caspases, PARP, BCL-2, Bax, etc.)
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Age associated cellular changes
- Mitochondrial dysfunction
- Genome instability
Mitochondrial DNA mutation
- mtDNA is a naked DNA prone to damage by ROS
- The DNA polymerase for mtDNA replication lack repairing function
- The nutation of mtDNA blocks the respiratory chain of cell that can cause further accumulation of free radicals
- Changes of mtDNA is closely associated with many diseases in elderly
Somatic mutation and genomic instability
- Normal condition damaged DNA is repaired by the DNA repair complexes immediately
- In old people repair mechanisms are compromised and degenerated
- Mutations and replication errors accumulate to a high level leading to ageing and death
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